Overall Survival Benefit With Upfront Daratumumab Plus Lenalidomide/Dexamethasone for Newly Diagnosed Transplant-Ineligible Patients With Multiple Myeloma

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In an updated analysis of the phase III MAIA trial, the addition of daratumumab to lenalidomide and dexamethasone resulted in a statistically significant overall survival benefit over lenalidomide/dexamethasone alone in patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplant. At the European Hematology Association 2021 Virtual Congress, these findings (LBA1901) were presented by Thierry Facon, MD, Professor of Hematology at Lille University Hospital in France.

“These results strongly support upfront daratumumab with lenalidomide and dexamethasone (D-Rd) as a new standard of care for patients with transplant-ineligible newly diagnosed multiple myeloma,” Dr. Facon said.

These results strongly support upfront daratumumab with lenalidomide and dexamethasone (D-Rd) as a new standard of care for patients with transplant-ineligible newly diagnosed multiple myeloma.
— Thierry Facon, MD. Photo by © ASH/Luke Franke 2018

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In the last MAIA update, which was reported at the 2020 ASH Annual Meeting & Exposition (Abstract 2276), D-Rd prolonged progression-free survival and second progression-free survival, but the overall survival data were not mature. Dr. Facon reported updated efficacy and safety results from a prespecified interim overall survival analysis after a median follow-up of approximately 56 months.

Findings in Overall Survival

At 5 years, with D-Rd, the risk of death was reduced by 32% (P = .0013) and the risk of disease progression or death was reduced by 47% (P < .0001), he reported.

“These data provide a new progression-free survival benchmark in patients with newly diagnosed multiple myeloma who are transplant-ineligible,” Dr. Facon said.

The benefits are all the more meaningful because the study population was elderly—99% were age 65 or older, and 44% were aged 75 to 90, said Dr. Facon, who emphasized that half or more of nontransplant elderly patients never receive subsequent therapy.

“This suggests the most effective therapy should be used upfront and not saved for relapse, at which time, additional genetic mutations conferring resistance may have been acquired,” he said.

Numerous Outcomes Improved

Numerous outcomes were significantly improved with the addition of daratumumab, as shown for D-Rd vs Rd:

  • Median overall survival: not reached in either arm; 5-year rates were 66.3% vs 53.1% (hazard ratio [HR] = 0.68, P = .0013)
  • Median progression-free survival: not reached vs 34.4 months; 5-year rates were 52.5% vs 28.7% (HR = 0.53, P < .0001)
  • Median time to next treatment: not reached vs 42.4 months (HR = 0.47, P < .0001)
  • Objective response rate: 93% vs 82%.

“Daratumumab plus lenalidomide/dexamethasone induced deeper responses, with significantly higher rates of complete responses or very good partial responses or better, and with 28 months or more of additional follow-up, responses deepened with continued daratumumab therapy,” Dr. Facon said.

More About MAIA

From 2015 to 2017, the MAIA trial enrolled 737 patients with newly diagnosed multiple myeloma (median age = 73 years) ineligible for high-dose chemotherapy and stem cell transplant. Patients were randomly assigned to receive D-Rd or Rd alone in 28-day cycles. In the D-Rd arm, patients received daratumumab at 16 mg/kg weekly for cycles 1 and 2, every 2 weeks for cycles 3­­ through 6, and every 4 weeks for cycle 7 on. In both arms, patients received lenalidomide at 25 mg on days 1 to 21 of each cycle and dexamethasone at 40 mg weekly. Patients continued treatment until disease progression.

At the time of the analysis, 42% of patients in the D-Rd arm remained on treatment, compared to 18% of the Rd arm. Median duration of receipt of the study treatment was 47.5 months and 22.6 months, respectively.

There were no new safety signals observed with continuous therapy and follow-up. The most common grade 3 or 4 adverse event in the D-Rd and Rd arms was neutropenia, seen in 54% vs 37% of patients, respectively. Of note, a lower percentage of grade 3 or 4 and serious treatment-emergent adverse events occurred after 24 months (compared with the first 24 months) in both treatment arms. More patients discontinued Rd because of toxicity (23% vs 13%).

The study authors concluded, “After almost 5 years of follow-up, a significant and clinically meaningful overall survival improvement was demonstrated with the use of D-Rd vs Rd in patients with newly diagnosed multiple myeloma who are transplant-ineligible, representing a 32% reduction in the risk of death. The significant progression-free survival benefit of D-Rd vs Rd from the primary analysis was maintained…. The favorable benefit-risk profile observed supports the use of D-Rd in transplant-ineligible patients with newly diagnosed multiple myeloma. These results, together with the overall survival benefit observed in ALCYONE, support the use of frontline daratumumab-based combination regimens to maximize progression-free survival for optimal long-term outcomes.”

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